Methods for treating cancer using pyrimidine and pyridine compounds with BTK inhibitory activity

ABSTRACT

The present invention provides methods of treating cancer using pyrimidine and pyridine compounds which are inhibitors of Bruton&#39;s tyrosine kinase (BTK).

RELATED APPLICATIONS

This application is a divisional of U.S. application U.S. Ser. No.15/343,570, filed on Nov. 4, 2016, which claims the benefit of U.S.Provisional applications U.S. Ser. No. 62/250,575, filed on Nov. 4,2015, U.S. Ser. No. 62/296,143, filed on Feb. 17, 2016, and U.S. Ser.No. 62/341,189, filed on May 25, 2016, the contents of which areincorporated herein by reference, in their entireties.

FIELD OF THE INVENTION

The invention relates to a series of pyrimidine and pyridine compoundsthat are useful as therapeutics in the treatment of cancer in mammals.More particularly, embodiments of the present invention describeirreversible kinase inhibitors including, but not limited to, inhibitorsof Bruton's tyrosine kinase (hereinafter referred to as: “BTK”). Methodsfor the preparation of the aforementioned compounds are disclosed inaddition to the incorporation of these compounds into pharmaceuticalcompositions that include the same.

BACKGROUND

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a wide variety of signaltransduction processes within the cell (Hardie, G. and Hanks, S. (1995)The Protein Kinase Facts Book. I and II, Academic Press, San Diego,Calif.). The kinases may be categorized into families by the substratesthey phosphorylate (e.g., protein-tyrosine, protein-serine/threonine,lipids, etc.). Sequence motifs have been identified that generallycorrespond to each of these kinase families (e.g., Hanks, S. K., Hunter,T., FASEB J., 9:576-596 (1995); Knighton, et al., Science, 253:407-414(1991); Hiles, et al., Cell, 70:419-429 (1992); Kunz, et al., Cell,73:585-596 (1993); Garcia-Bustos, et al., EMBO J., 13:2352-2361 (1994)).Protein kinases may be characterized by their regulation mechanisms.These mechanisms include, for example, autophosphorylation,transphosphorylation by other kinases, protein-protein interactions,protein-lipid interactions, and protein-polynucleotide interactions. Anindividual protein kinase may be regulated by more than one mechanism.

Kinases regulate many different cell processes including, but notlimited to, proliferation, differentiation, apoptosis, motility,transcription, translation and other signalling processes, by addingphosphate groups to target proteins. These phosphorylation events act asmolecular on/off switches that can modulate or regulate the targetprotein biological function. Phosphorylation of target proteins occursin response to a variety of extracellular signals (hormones,neurotransmitters, growth and differentiation factors, etc.), cell cycleevents, environmental or nutritional stresses, etc. The appropriateprotein kinase functions in signalling pathways to activate orinactivate (either directly or indirectly), for example, a metabolicenzyme, regulatory protein, receptor, cytoskeletal protein, ion channelor pump, or transcription factor. Uncontrolled signalling due todefective control of protein phosphorylation has been implicated in anumber of diseases, including, for example, inflammation, cancer,allergy/asthma, diseases and conditions of the immune system, diseasesand conditions of the central nervous system, and angiogenesis.

BTK, a member of the Tec family of non-receptor tyrosine kinases, is asignaling enzyme expressed in all hematopoietic cell types except Tlymphocytes and natural killer cells. BTK plays a well documented rolein the B-cell signaling pathway linking cell surface B-cell receptorstimulation to downstream intracellular responses. BTK is also aregulator of B-cell development, activation, signaling, and survival(Kurosaki, Curr Op Imm, 2000, 276-281; Schaeffer and Schwartzberg, CurrOp Imm 2000, 282-288). In addition, BTK exerts a physiological effectthrough other hematopoietic cell signaling pathways, e.g., Toll likereceptor (TLR) and cytokine receptor-mediated TNF-α production inmacrophages, IgE receptor (FcepsilonRI) signaling in Mast cells,inhibition of Fas/AP0-1 apoptotic signaling in B-lineage lymphoid cells,and collagen-stimulated platelet aggregation. BTK has an ATP-bindingpocket with high similarity to Src-family kinases, such aslymphocyte-specific protein tyrosine kinase (Lck) and Lyn. Comparing BTKto other kinases one finds a conserved cysteine residue, Cys-481, in 11of 491 kinases, specifically members of the Tee and EGFR (epidermalgrowth factor receptor) kinase families.

BTK plays important roles in the development, differentiation,activation and proliferation of B cells, as well as their antibody andcytokine generation. In addition, Btk plays a central role in otherimmunological processes such as cytokine production by neutrophils, mastcells and monocytes, degranulation of neutrophils and mast cells as wellas differentiation/activation of osteoclasts. B-cell activation, breakof tolerance and auto-antibody production, on one hand and theproinflammatory milieu originated from exacerbated activation ofmonocytes, neutrophils and mast cells, on the other hand, are crucial inthe etiology of autoimmune diseases, including (but not limited to)rheumatoid arthritis and systemic lupus erythematosus.

Reversible kinase inhibitors have been developed into therapeuticcompounds. These reversible inhibitors, however, have decideddisadvantages. Many reversible inhibitors of kinases interact with theATP-binding site. Given the structure of the ATP-binding sites arehighly conserved among kinases, it has been difficult to develop areversible inhibitor that selectively inhibits a desired (i.e., target)kinase. Moreover, given that many reversible kinase inhibitors readilydissociate from their target polypeptide(s), maintaining inhibition overextended periods of time can be difficult. When using reversible kinaseinhibitors as therapeutics, therefore, often times near toxic dosagesand/or frequent dosing is required to achieve the intended biologicaleffect.

What is needed, therefore, are irreversible kinase inhibitors thatcovalently bind to their target polypeptide(s) without (substantially)binding to off-target polypeptides and, thereby, exerting undesirableoff-target effects.

SUMMARY OF THE INVENTION

The present invention is directed towards compounds of the formulaepresented herein for the treatment and/or prophylaxis of cancer,including Non-Hodgkin's Lymphoma mantle cell lymphoma and Non-Hodgkins'sLymphoma diffuse large b-cell lymphoma, including abc subtype.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the average percent inhibition of compound (2) at each doselevel across 11 primary CLL patient samples.

FIG. 2 show inhibition of compound (2) in an ABC-DLBCL assay, across 6cell lines.

FIG. 3 show inhibition of compound (2) in an MCL assay, across 6 celllines.

FIG. 4a shows the In vivo efficacy study in MCL model. The objective wasto determine anti-tumor effects and dose response. MCL cell lines: Mino,s.c. xenograft models. Mouse strain: nu/nu mice. Treatments start at150-200 mm³ tumor volume.

FIGS. 4b and 4c : Mino: BTK inhibitor in MCL model, tumor volume andbody weight.

FIGS. 4d and 4e : Mino: BTK inhibitor in MCL model, tumor volume andbody weight.

DESCRIPTION OF THE INVENTION

The present invention provides a series of novel pyrimidine and pyridinekinase inhibitors. In some embodiments said kinase inhibitors areirreversible inhibitors of tyrosine kinases. In preferred embodiments,said irreversible kinase inhibitors inhibit BTK. While it is notintended that the compounds described by the present invention belimited to any specific mechanism of action, in some embodiments saidirreversible kinase inhibitors exert a physiological effect by forming acovalent bond with Cys 481 in BTK. Significantly, this Cys 481 in BTKfinds homologs in other kinases. Embodiments of the present inventionalso described methods for synthesizing said irreversible inhibitors,methods for using said irreversible inhibitors in the treatment ofdiseases (including hyperproliferative diseases). Further described arepharmaceutical formulations that include an irreversible kinaseinhibitor including pharmaceutically acceptable salts, solvates orprodrugs thereof, that are kinase inhibitors and useful in the treatmentof the above mentioned diseases.

In one aspect, the invention provides a method for the treatment and/orprophylaxis of cancer, comprising administering to a subject a compoundof Formula (I):

-   -   in which:    -   X denotes CH or N,    -   R¹ denotes NH₂, CONH₂ or H,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NR⁵[C(R⁵)₂]_(n)Het², NR⁵[C(R⁵)₂]_(n)Cyc, Het²,        O[C(R⁵)₂]_(n)Ar², NR⁵[C(R⁵)₂]_(n)Ar², O[C(R⁵)₂]_(n)Het²,        NR⁵(CH₂)_(p)NR⁵R⁶, O(CH₂)_(p)NR⁵R⁶ or NR⁵(CH₂)_(p)CR⁷R⁸NR⁵R⁶,    -   R⁴ denotes H, CH₃ or NH₂,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃C≡CCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N≡CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        CH₂═CHSO₂, ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,        CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA        and/or OHet³ (CH₂),    -   Ar² denotes phenyl, naphthyl or pyridyl each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶, Hal, OAr³,        (CH₂)_(n)NH₂, (CH₂)_(n)NHCOA and/or Het³,    -   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by OH, OA, Hal, ON and/or A,    -   Het¹ denotes a mono- or bicyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,    -   Het² denotes a mono- or bicyclic saturated heterocycle having 1        to 4 N, O and/or S atoms, which may be unsubstituted or mono-,        di- or trisubstituted by R⁶, Het³, CycSO₂, OH, Hal, COOH, OA,        COA, COHet³, CycCO, SO₂ and/or ═O    -   Het³ denotes a monocyclic unsaturated, saturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes a bi- or tricyclic unsaturated, saturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di-, tri- or tetrasubstituted by        A, NO₂, Hal and/or ═O,    -   Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted, monosubstituted or disubstituted by R⁶ and/or OH        and which may comprise a double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7 H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6,    -   and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

In general, all residues which occur more than once may be identical ordifferent, i.e. are independent of one another. In other embodiments,the residues and parameters have the meanings indicated for the Formula(I), unless expressly indicated otherwise.

In certain embodiments, Het¹ denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,azabicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl,benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl,tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl, dihydropyridylor dihydrobenzodioxinyl, each of which is unsubstituted or mono-, di- ortrisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³.

In certain embodiments, Het¹ denotes pyrazolyl, pyridyl, pyrimidinyl,dihydropyridyl or dihydrobenzodioxinyl, each of which is unsubstitutedor mono-, di- or trisubstituted by R⁶, O(CH₂)_(n)Ar³ and/or(CH₂)_(n)Ar³.

In certain embodiments, Het² denotes piperidinyl, piperazinyl,pyrrolidinyl, rnorpholinyl, azabicyclo[3.2.1]octyl,azabicyclo[2.2.2]octyl, 2,7-diazaspiro[3.5]nonyl,2,8-diazaspiro[4.5]decyl, 2,7-diazaspiro[4.4]nonyl,3-azabicylo[3.1.0]hexyl, 2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl,7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl, azetidinyl,azepanyl, tetrahydrofuryl, dioxolanyl, tetrahydrothienyl,tetrahydroimidazolyl, tetrahydropyrazolyl, tetrahydropyridyi, each ofwhich is unsubstituted or mono-, di- or trisubstituted by R⁶, Het³,CycSO₂, OH, OA, COA, COHet³, CycCO, SO₂ and/or ═O.

In certain embodiments, Het³ denotes piperidinyl, piperazinyl,pyrrolidinyl, morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl,pyrazolyl, oxazolyl, isoxazoly, thiazolyl, isothiazolyl, pyridyl,pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl,tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl,tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl,tetrahydropyridyl or dihydropyridyl, each of which may be unsubstitutedor mono-, di- or trisubstituted by Hal, A and/or ═O.

In certain embodiments, Het³ denotes piperidinyl, pyrrolidinyl,rnorpholinyl, furyl, thienyl, pyrrolyl, irnidazalyl, pyrazolyl, pyridyl,pyrimidinyl, dihydropyrrolyl, dihydropyrazolyl or dihydropyridyl, eachof which may be unsubstituted or mono-, di- or trisubstituted by Hal, Aand/or ═O.

In certain embodiments, Het⁴ denotes hexahydrothieno[3,4-d]imidazolyl,benzo[c][1,2,5]oxadiazolyl or5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-iudyl, each ofwhich may be unsubstituted or mono-, di-, tri- or tetrasubstituted by A,NO₂, Hal and/or ═O.

In certain embodiments,

-   -   X denotes CH or N,    -   R¹ denotes NH₂, CONH₂ or H,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NR⁵[C(R⁵)₂]_(n)Het², NR⁵[C(R⁵)₂]_(n)Cyc, Het²,        O[C(R⁵)₂]_(n)Ar², NR⁵[C(R⁵)₂]_(n)Ar², O[C(R⁵)₂]_(n)Het²,        NR⁵(CH₂)_(p)NR⁵R⁶, O(CH₂)_(p)NR⁵R⁶ or NR⁵(CH₂)_(p)CR⁷R⁸NR⁵R⁶,    -   R⁴ denotes H,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH═CHCONH, HC≡CCO, CH₃C≡CCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N≡CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        CH₂═CHSO₂, ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,        CH₂═CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA        and/or OHet³ (CH₂),    -   Ar² denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, OAr³, (CH₂)_(n)NH₂,        (CH₂)_(n)NHCOA and/or Het³,    -   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by OH, OA, Hal, CN and/or A,    -   Het¹ denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, furyl, thienyl, pyrrolyl, irnidazolyl, pyrazolyl,        oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,        pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,        pyridazinyl, pyrazinyl, benzimidazolyl, benzotriazolyl, indolyl,        benzo-1,3-dioxolyl, indazolyl, azabicyclo[3.2.1]octyl,        azabicyclo[2.2.2]octyl, imidazolidinyl, azetidinyl, azepanyl,        benzo-2,1,3-thiadiazolyl, tetrahydrofuryl, dioxolanyl,        tetrahydrothienyl, dihydropyrrolyl, tetrahydroimidazolyl,        dihydropyrazolyl, tetrahydropyrazolyl, tetrahydropyridyl,        dihydropyridyl or dihydrobenzodioxinyl, each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,    -   Het² denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, azabicyclo[3.2.1]octyl, azabicyclo[2.2.2]octyl,        2,7-diazaspiro[3.5]nonyl, 2,8-diazaspiro[4.5]decyl,        2,7-diazaspiro[4.4]nonyl, 3-azabicylo[3.1.0]hexyl,        2-azaspiro[3.3]heptyl, 6-azaspiro[3.4]octyl,        7-azaspiro[3.5]nonyl, 5-azaspiro[3.5]nonyl, imidazolidinyl,        azetidinyl, azepanyl, tetrahydrofuryl, dioxolanyl,        tetrahydrothienyl, tetrahydroimidazolyl, tetrahydropyrazolyl,        tetrahydropyridyl, each of which is unsubstituted or mono-, di-        or trisubstituted by R⁶, Het³, CycSO₂, OH, OA, COA, COHet³,        CycCO, SO₂ and/or ═O,    -   Het³ denotes piperidinyl, piperazinyl, pyrrolidinyl,        morpholinyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl,        oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl,        pyrimidinyl, triazolyl, tetrazolyl, oxadiazolyl, thiadiazolyl,        pyridazinyl, pyrazinyl, imidazolidinyl, azetidinyl, azepanyl,        tetrahydrofuryl, dioxolanyl, tetrahydrothienyl, dihydropyrrolyl,        tetrahydroimidazolyl, dihydropyrazolyl, tetrahydropyrazolyl,        tetrahydropyridyl or dihydropyridyl, each of which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes hexahydrothieno[3,4-d]imidazolyl,        benzo[c][1,2,5]oxadiazolyl or        5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-uidyl, each        of which may be unsubstituted or mono-, di-, tri- or        tetrasubstituted by A, NO₂, Hal and/or ═O,    -   Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted or monosubstituted by R⁶ and which may comprise a        double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7 H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of cancer, comprising administering to asubject a compound of Formula (II):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

-   X is H or CH₃ or NH₂,-   Y is H, Hal or is absent,-   B is N or CH,-   E is NH₂ or H,-   W is NR, O or a cyclic amine,-   Z is, independently, CH₂, CH₃, CH₂—CH₂, CH—CH₂, H, NH or is absent,-   “linker” is (CH₂)_(n), wherein: _(n) is 1, 2 or 3 or an optionally    substituted group selected from a phenyl ring, an aryl ring,    heteroaryl ring, branched or unbranched alkyl group, a 5-6 membered    monocyclic heteroaryl ring having 1-4 heteroatoms independently    selected from nitrogen, or oxygen, a 4-7 membered saturated or    partially unsaturated heterocycle having 1-3 heteroatoms    independently selected from nitrogen, or oxygen, or a 7-10 membered    bicyclic saturated or partially unsaturated heterocyclic ring having    1-5 heteroatoms independently selected from nitrogen, or oxygen, or    a 7-10 membered bicyclic saturated or partially unsaturated    heterocyclic ring having 1-5 heteroatoms attached to a hetero    saturated ring. Linkers may also be cycloalkanes optionally    substituted by heteroatoms (independently selected from nitrogen, or    oxygen), cycloalkanes optionally substituted with —NH or OH, fused    or bridged rings or optionally substituted spirocyclic rings that    optionally contain heteroatoms,-   A is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1,    2, 3 or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton C    atoms, which may be unsubstituted or, independently of one another,    mono-, di- or trisubstituted by Hal, OH or OR,-   Hal is F, Cl, Br or I,-   R is independently hydrogen, oxygen or an optionally substituted    group selected from C₁₋₆ linear or cyclic aliphatic, benzyl, phenyl,    a phenyl group optionally substituted with 1, 2 or 3 O atoms, a 4-7    membered heterocylic ring having 1-2 heteroatoms independently    selected from nitrogen, oxygen, or a 5-6 membered monocyclic    heteroaryl ring having 1-4 heteroatoms independently selected from    nitrogen, or oxygen or a mono- or bicyclic aromatic homo- or    heterocycle having 0, 1, 2, 3 or 4 N, O atoms and 5, 6, 7, or 8 C    skeleton atoms, which may be unsubstituted or, independently of one    another, mono-, di- or trisubstituted by Hal, A, OH, NH₂, nitrile,    and/or CH(Hal)₃ or is an unbranched or branched linear alkyl having    1, 2, 3, 4, 5, 6, 7 or 8 C atoms, in which one or two CH₂ groups may    be replaced by an O atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—,    —CONH—, NHCO— or —CH═CH— group, and in which 1-3 H atoms may be    replaced by Hal,-   R^(q) is selected from —R, -A, halogen, —OR, —O(CH₂)_(r)OR, —R(NH),    —NO₂, —C(O)R, —CO₂R, —C(O)N(R)₂, —NRC(O)R, —NRC(O)NR₂, —NRSO₂R, or    —N(R)₂,-   r is 1-4,-   n is 0-4, and-   Q is an electrophilic group such as those listed in Table 1 wherein    said electrophilic groups may further comprise a warhead.

As used herein the term “warhead” refers to a part, functional group orsubstituent of the compounds as claimed in the present invention,wherein, said part, functional group or substituent covalently binds toan amino acid (such as cysteine, lysine, or any other amino acid, eithernative or modified, that can form said covalent bond) that is present,for example, in the binding region within a given ligand wherein saidwarhead binds with said ligand, wherein the covalent binding betweensaid warhead and the binding region of said target protein occurs underconditions wherein a physiological function of said protein isirreversibly inhibited.

While it is not intended that the present invention be limited to aspecific group for substituent Q, as set out in Formula (II) above, incertain embodiments substituent C is selected from the groups set out inTable 1. All compounds, in Table 1, appearing within a box are not“warheads” as defined above.

TABLE 1

wherein,

denotes the bonding point of Q to Z in Formula (II).

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of cancer, comprising administering to asubject a compound of Formula (III):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

-   X is O or NH,-   Y is N or CH,-   W is H, NH₂ or CONH₂,-   Q is H or NH₂,-   R¹ is L¹-R⁴-L²-R⁵,-   R² is M¹-S⁴-M²-S⁵-   L¹ is a single bond, methylene, or cyclic A which may be mono- or    disubstituted with N or NH₂,-   R⁴ is Ar, A or cyclic A which may be mono- or disubstituted with N,    —O— or Hal,-   R⁵ is Ar, A or cyclic A which may be mono- or disubstituted with N,    —O— or Hal or is absent. In preferred embodiments, R⁵ is selected    from the group consisting of 2-fluoropyridine,    1-methylpyridin-2(1H)-one and 2-chloropyridine,-   L² is H, —O—, substituted or unsubstituted C₁-C₄alkyl, substituted    or unsubstituted C₁₋₄ heteroalkyl, C₁-C₆alkoxyakyl,    C₁-C₈alkylaminoalkyl, substituted or unsubstituted aryl, substituted    or unsubstituted heteroaryl, C₁-C₄alkyl(aryl),    C₁-C₄alkyl(heteroaryl), C₁-C₄alkyl(C₃-C₈cycloalkyl), or    C₁-C₄alkyl(C₂-C₈ heterocycloalkyl). In some embodiments, L² is    —CH₂—O—(C₁-C₃alkyl), —CH₂—N(C₁-C₃alkyl)₂, C₁-C₄alkyl(phenyl), or    C₁-C₄alkyl (5- or 6-membered heteroaryl). In some embodiments L² is    -A-. In some embodiments L² is absent. In preferred embodiments of    the present invention L² is selected from the group consisting of    but-3-en-2-one, propan-2-one, (E)-5-(dimethylamino)pent-3-en-2-one,    (E)-pent-3-en-2-one, pent-3-yn-2-one, 1-chloropropan-2-one,    (methylsulfonyl)ethane,    (E)-5-((2-methoxyethyl)(methyl)amino)pent-3-en-2-one or    (Z)-pent-3-en-2-one,-   M₁ is a single bond,-   S⁴ is Ar, A or cyclic A which may be mono- or disubstituted with N,    —O— or Hal. In preferred embodiments of the present invention S⁴ is    a heteroaromatic 5 to 6 member ring,-   M² O, NH, CH₂ or is absent,-   S⁵ is H, Ar, A or cyclic A which may be mono- or disubstituted with    N, —O—, Hal. In certain embodiments of the present invention S⁵ is    selected from the group consisting of but-3-en-2-one, benzene,    (E)-5-(dimethylamino)pent-3-en-2-one, ethylbenzene,    1-ethyl-2-methoxybenzene, aniline and    (E)-5-morpholinopent-3-en-2-one. In some embodiments of the present    invention S₅ is absent,-   Ar is a mono- or bicyclic aromatic homo- or heterocycle having 0, 1,    2, 3 or 4 N, and/or O atoms and 5, 6, 7, 8, 9, or 10 skeleton atoms,    which may be unsubstituted or, independently of one another, mono-,    di- or trisubstituted by Hal, A, OH, OA, NH₂, NHA, NA₂, NO₂, CN,    OCN, COOH, COOA, CONH₂, CONHA, CONA₂, NHCOA, NHCONHA, NHCONH, CHO    and/or COA, and in which a ring N-atom may be substituted by an    O-atom to form an N-oxide group and in which in the case of a    bicyclic aromatic cycle on of the two rings may be partly saturated,-   A is unbranched or branched linear or cyclic alkyl having 1, 2, 3,    4, 5, 6, 7 or 8 C atoms, in which one or two CH₂ groups may be    replaced by an O atom and/or by an —NH—, —CO—, —NHCOO—, —NHCONH—.    —N(LA)-, —CONH—, —NHCO— or —CH═CH— group,-   LA is unbranched or branched, linear alkyl having 1, 2, 3 or 4 C    atoms, wherein 1, 2 or 3 H atoms may be replaced by Hal,-   Hal is F, Cl, Br or I.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of cancer, comprising administering to asubject a compound of Formula (IV):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof, wherein:

-   Z is N or CH,-   X is O or NH, and-   R³ is selected from the group consisting of the following    structures:

wherein, “R” denotes the bonding point to Z in Formula IV.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of cancer, comprising administering to asubject a compound of Formula (V):

and pharmaceutically acceptable salts, solvates, solvates of salts, orprodrugs thereof,

-   -   in which:    -   X denotes CH or N,    -   R¹ denotes NR⁵[C(R⁵)₂]_(n)Het²,    -   R² denotes Hal, Ar¹ or Het¹,    -   R³ denotes NH₂,    -   R⁴ denotes H, CH₃ or NH₂,    -   R⁵ denotes H or alkyl having 1, 2, 3 or 4 C atoms,    -   R⁶ N(R⁵)₂CH₂CH═CHCONH, Het³CH₂CH═CHCONH, CH₂═CHCONH(CH₂)_(n),        Het⁴(CH₂)_(n)COHet³-diyl-CH₂CH—CHCONH, HC≡CCO, CH₃C≡CCO,        CH₂═CH—CO, CH₂═C(CH₃)CONH, CH₃CH═CHCONH(CH₂)_(n),        N≡CCR⁷R⁸CONH(CH₂)_(n), Het⁴NH(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH        Het⁴(CH₂)_(p)CONH(CH₂CH₂O)_(p)(CH₂)_(p)COHet³-diyl-CH₂CH═CHCONH,        CH₂—CHSO₂, ACH═CHCO, CH₃CH═CHCO,        Het⁴(CH₂)_(p)CONH(CH₂)_(p)Het³-diyl-CH₂CH═CHCONH, Ar³CH═CHSO₂,        CH₂—CHSO₂NH or N(R⁵)CH₂CH═CHCO,    -   R⁷, R⁸ denote together alkylene having 2, 3, 4, or 5 C atoms,    -   Ar¹ denotes phenyl or naphthyl, each of which is unsubstituted        or mono-, di- or trisubstituted by R⁶, Hal, (CH₂)_(n)NH₂,        CONHAr³, (CH₂)_(n)NHCOA, O(CH₂)_(n)Ar³, OCyc, A, COHet³, OA        and/or OHet³ (CH₂),    -   Ar² denotes phenyl, naphthyl or pyridyl each of which is        unsubstituted or mono-, di- or trisubstituted by R⁶, Hal, OAr³,        (CH₂)_(n)NH₂, (CH₂)_(n)NHCOA and/or Het³,    -   Ar³ denotes phenyl, which is unsubstituted or mono-, di- or        trisubstituted by OH, OA, Hal, CN and/or A,    -   Het¹ denotes a mono- or bicyclic saturated, unsaturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di- or trisubstituted by R⁶,        O(CH₂)_(n)Ar³ and/or (CH₂)_(n)Ar³,    -   Het² denotes a mono- or bicyclic saturated heterocycle having 1        to 4 N, O and/or S atoms, which may be unsubstituted or mono-,        di- or trisubstituted by R⁶, Het³, CycSO₂, OH, Hal, COOH, OA,        COA, COHet³, CycCO, SO₂ and/or ═O,    -   Het³ denotes a monocyclic unsaturated, saturated or aromatic        heterocycle having 1 to 4 N, O and/or S atoms, which may be        unsubstituted or mono-, di- or trisubstituted by Hal, A and/or        ═O,    -   Het⁴ denotes a bi- or tricyclic unsaturated, saturated or        aromatic heterocycle having 1 to 4 N, O and/or S atoms, which        may be unsubstituted or mono-, di-, tri- or tetrasubstituted by        A, NO₂, Hal and/or ═O,    -   Cyc denotes cyclic alkyl having 3, 4, 5 or 6 C atoms, which is        unsubstituted, monosubstituted or disubstituted by R⁶ and/or OH        and which may comprise a double bond,    -   A denotes unbranched or branched alkyl having 1-10 C atoms, in        which 1-7 H atoms may be replaced by F and/or Cl and/or in which        one or two non-adjacent CH₂ and/or CH-groups may be replaced by        O, NH and/or by N,    -   Hal denotes F, Cl, Br or I,    -   n denotes 0, 1, 2, 3 or 4,    -   p denotes 1, 2, 3, 4, 5 or 6,    -   and pharmaceutically usable salts, tautomers and stereoisomers        thereof, including mixtures thereof in all ratios.

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of cancer, comprising administering to asubject a compound selected from Table 2:

TABLE 2 No. Chemical Name “A1”(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one “A2”(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)piperidin-1-yl)prop-2-en-1-one “A3”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)phenyl)acrylamide “A4”(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A5”N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pyrrolidin-3-yl)methyl)acrylamide “A6”1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one “A7”N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-4-yl)methyl)acrylamide “A8”4-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pipendine-1-carbonyl)-1-methylpyridin- 2(1H)-one “A9”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-yn-1-one “A10”5-(4-phenoxyphenyl)-N4-((1-(vinylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine “A11”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-((2-methoxyethyl)(methyl)amino)but-2-en-1-one “A12”(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(2-fluoropyridin-3-yl)methanone “A13”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one “A14”N4-((1-(cyclopropylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A15”(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-en-1-one “A16”1-(4-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one “A17”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidln-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one “A18”N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)amino)ethyl)acrylamide“A19” (R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyrrolidin-1-yl)prop-2-en-1-one “A20”N-(1-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclopentyl)acrylamide “A21”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A22”1-(4-(((5-fluoro-3-(4-phenoxyphenyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A23”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pipendin-1-yl)ethanone “A24”(E)-7-(3-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)-3-oxopropyl)-5,5-difluoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide “A25”1-(4-(((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A26”(S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A27”N-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)oxy)ethyl)acrylamide“A28” (S)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A29”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-methylprop-2-en-1-one “A30”(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclohex-1-en-1-yl)methanone “A31”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-methylbut-2-en-1-one “A32”(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclopent-1-en-1-yl)methanone “A33”1-(4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A34”1-(4-(((6-amino-5-(4-(3-fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A35”(E)-7-(3-((2-(4-(4-((3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)amino)-4-oxobut-2-en-1-yl)piperazin-1-yl)ethyl)amino)-3-oxopropyl)-5,5-difiuoro-1,3-dimethyl-5H-dipyrrolo[1,2-c:2′,1′-f][1,3,2]diazaborinin-4-ium-5-uide “A36”1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A37”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one “A38”(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A39”1-(4-(((6-amino-5-(4-(phenylamino)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A40”1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1H-pyrrol-2(5H)-one “A41”1-(4-(((6-amino-5-(4-benzylphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A42”(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)(cyclobut-1-en-1-yl)methanone “A43”(Z)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)but-2-en-1-one “A44”1-(4-(((6-amino-2-methyl-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A45”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2-chloroethanone “A46”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-yn-1-one “A47”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)(methyl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A48”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one “A49”N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide “A50”N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)amino)butyl)acrylamide“A51” N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A52”1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azepan-1-yl)prop-2-en-1-one “A53”N-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A54”(E)-5-(4-phenoxyphenyl)-N4-((1-(styrylsulfonyl)piperidin-4-yl)methyl)pyrimidine-4,6-diamine “A55”N4-((1-(methylsulfonyl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A56”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-2,3-dihydroxypropan-1-one “A57”4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-2-one “A58”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)ethenesulfonamide “A59”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)propyl)acrylamide “A60”N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide “A61”(R)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-yn-1-one “A62”(R,E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1- one “A63”(E)-N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)-4-(dimethylamino)but-2-enamide “A64”N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)propiolamide “A65”(S)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one “A66”(R)-1-(2-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one “A67”N-(3-((6-amino-5-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A68”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-yn-1-one “A69”N-(3-((6-amino-5-(1-(4-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A70”N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)phenyl)acrylamide “A71”(E)-1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)-4-(dimethylamino)but-2-en-1-one “A72”N-(3-((6-amino-5-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A73”(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A74”(R,E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A75”1-(trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypyrrolidin-1-yl)prop-2-en-1-one “A76”1-(4-(((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A77”1-(4-(((6-amino-5-(4-fluorophenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A78”1-(4-(((6-amino-5-(4-(trifluoromethoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A79”1-(4-(((6-amino-5-(4-(4- (trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A80”1-(4-(((6-amino-5-(4-(4-(fluorophenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A81”1-(4-(((6-amino-5-(4-(trifluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A82”1-(4-(((6-amino-5-(3,4-dimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A83”1-(4-(((6-amino-5-(3,4,5-trimethoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A84”1-(4-(((6-amino-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A85”1-(4-(((6-amino-5-(4-methoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A86”4-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A87”1-(4-(((6-amino-5-(2,5-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A88”1-(4-(((6-amino-5-(2,3-difluoro-4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A89”1-(4-(((6-amino-5-(4-((1-methylpiperidin-4-yl)oxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A90” 1-(4-(((6-amino-5-(4-phenoxy-2-(tnfluoromethyl)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A91”1-(2-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[3.5]nonan-7-yl)prop-2-en-1-one “A92”1-(8-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decan-2-yl)prop-2-en-1-one “A93”1-(7-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)-2,7-diazaspiro[4.4]nonan-2-yl)prop-2-en-1-one “A94”1-(4-(((6-amino-5-(4-(4-hydroxyphenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A95”1-(4-(((6-amino-5-(4-(3- (trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A96”1-(4-(((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A97”1-(4-(((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A98”1-(4-(((6-amino-5-(4-(p-tolyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A99”1-(4-(((6-amino-5-(4-(cyclohexyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A100”N4-((1R,5S,6r)-3-azabicyclo[3.1.0]hexan-6-ylmethyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine hydrochloride “A101”(3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-3-ol hydrochloride “A102”(E)-1-(6-((6-amino-5-chloropyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one “A103”1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-en-1-one “A104”1-(3-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)azetidin-1-yl)prop-2-yn-1-one “A105”(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one “A106”1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A107”1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A108”1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)but-2-yn-1-one “A109”1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one “A110”1-((3S,4S)-4-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-yn-1-one “A111”1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one “A112”1-(6-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-yn-1-one “A113”1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-en-1-one “A114”1-(6-((6-amino-5-(4-(pyridin-4-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A115”1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)prop-2-yn-1-one “A116”1-(6-((6-amino-5-(1-(pyridin-4-ylmethyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en- 1-one“A117” N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A118”N-((1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A119”N4-(2-((2-chloroethyl)sulfonyl)-2-azaspiro[3.3]heptan-6-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A120”1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl) prop-2-en-1-one “A121”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-methoxypipendin-1-yl)prop-2-en-1-one “A122”N-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)spiro[3.3]heptan-2-yl)acrylamide “A123”1-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-7-azaspiro[3.5]nonan-7-yl)prop-2-en-1-one “A124”1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A125”1-(8-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-azaspiro[3.5]nonan-5-yl)prop-2-en-1-one “A126”(E)-1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A127”(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-2-azaspiro[3.3]heptan-2-yl)-4-(dimethylamino)but-2-en-1-one “A128”3-((6-Amino-5-chloro-pyrimidin-4-ylamino)-methyl)- benzoic acid methylester “A129” Trans-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester “A130”(1R,3S)-3-(6-Amino-5-chloro-pyrimidin-4-ylamino)- cyclohexanecarboxylicacid methyl ester “A131”3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)- methyl)-benzoicacid methyl ester “A132”Trans-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester “A133”(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methyl ester “A134”-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)- methyl)-benzoicacid “A135” (1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid “A136”(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid “A137”(4-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-phenyl)-N-methoxy-N-methyl-acetamide “A138”3-((6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-ylamino)-methyl)-N-methoxy-N-methyl-benzamide “A139”(1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide “A140”(1R,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexanecarboxylic acid methoxy-methyl-amide “A141”1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-yn-1-one “A142”1-(3-((6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-methyl)-phenyl)-but-2-en-1-one 'A143”1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-propenone “A144”1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one “A145”1-((1S,3S)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one “A146”1-((1S,3R)-3-(6-Amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-en-1-one “A147”1-((1S,3R)-3-(6-amino-5-(4-phenoxyphenyl)-pyrimidin-4-ylamino)-cyclohexyl)-but-2-yn-1-one “A148”(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)prop-2-en-1-one “A149”N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)acrylamide “A150”1-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A151”(E)-N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide “A152”(E)-N-(3-((2-amino-3-(4-(benzyloxy)phenyl)pyridin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide “A153”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(dimethylamino)but-2- en-1-one “A154”N-cis-4-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A155”4-(4-(((1-acryloylpyrrolidin-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide “A156”1-(3-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A157” 4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide “A158”N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)-4-fluorophenyl)acrylamide “A159”4-(4-((cis-4-acrylamidocyclohexyl)amino)-6-aminopyrimidin-5-yl)-N-phenylbenzamide “A160”(E)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A161”N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide “A162”N-(3-((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A163”N-(3-((6-amino-5-(3-sulfamoylphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A164”N-(3-((6-amino-5-(3-(trifluoromethoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A165”N-(3-((6-amino-5-(6-(2-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A166”N-(3-((6-amino-5-(6-(4-fluorophenoxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acryiamide “A167”N-(6-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-2- yl)acrylamide“A168” 1-(4-(((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A169”1-(4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-4-hydroxypiperidin-1-yl)prop-2-en-1-one “A170”1-((3S,4S)-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)prop-2-en-1-one “A171”1-(4-(((6-amino-2′-phenoxy-[5,5′-bipyrimidin]-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A172”N-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A173”N-((1S,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A174”N-((1R,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A175”N-((1R,3R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A176”N-((1S,3S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acryiamide “A177”N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)bicyclo[2.1.1]hexan-1-yl)acrylamide “A178”(R)-N4-(1-((perfluorophenyl)sulfonyl)pyrrolidin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A179”(R)-N4-(1-((perfluorophenyl)sulfonyl)pipendin-3-yl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A180”(R)-1-(3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A181”N-(cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclopentyl)acrylamide “A182”N-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)cyclobutyl)acrylamide “A183”N-(3-((6-amino-5-(1-(3,5-difluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A184”N-(3-((6-amino-5-(1-(2-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A185”1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)azetidin-1-yl)prop-2-en-1-one “A186”N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyridin-3-yl)acrylamide “A187”N-(3-((6-amino-5-(1-(4-fluorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A188”N-((1R,3S,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-hydroxycyclohexyl)acrylamide(racemic) “A189”N-(5-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide “A190”N-(3-((6-amino-5-(1-(3-methylbenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A191”N-(3-((6-amino-5-(1-(3-chlorobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A192”(R)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one “A193”(S)-1-(2-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)morpholino)prop-2-en-1-one “A194”N-(3-((6-amino-5-(1-(2-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A195”N-(3-((6-amino-5-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A196”(R)-1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A197”N-(5-((6-amino-5-(4-(4-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)pyridin-3-yl)acrylamide “A198”N-(3-((6-amino-5-(1-(3-methoxybenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acryiamide “A199”4-(4-(4-((((3S,4S)-1-acryloyl-3-hydrpxypiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A200”(R)-4-(4-(4-((4-acryloylmorphoiin-2-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitriie “A201”(R)-4-(4-(4-((1-acryloylpyrrolidin-3-yl)methoxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A202”4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)oxy)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A203”N-(3-((6-amino-5-(1-(3-cyanobenzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A204”1-((3S,5S)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one “A205”1-((3R,5R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-5-fluoropiperidin-1-yl)prop-2-en-1-one “A206” methyl3-((4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-1H-pyrazol-1-yl)methyl)benzoate “A207”4-(4-(4-((2-acryloyl-2-azaspiro[3.3]heptan-6-yl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A208”4-(4-(4-(((8-acryloyl-8-azabicyclo[3.2.1]octan-3-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A209”1-(3-(((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)methyl)-8-azabicyclo[3.2.1]octan-8-yl)prop-2-en-1-one “A210”1-((3R,4R)-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-4-hydroxypiperidin-1-yl)prop-2-en-1-one(racemic) “A211”N-(3-((6-amino-5-(1-(3-(methylsulfonyl)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A212”N-(3-((6-amino-5-(1-(3-(dimethylamino)benzyl)-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A213”N-(3-((6-amino-5-(4-(3-cyanophenoxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A214”3-(4-(4-(((1-acryloylpiperidin-4-yl)methyl)amino)-6-aminopyrimidin-5-yl)phenoxy)benzonitrile “A215”1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)but-2-yn-1-one “A216”1-acryloyl-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid “A217”(E)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-1-(4-(dimethylamino)but-2-enoyl)piperidine-4-carboxylic acid “A218”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3-fluoroazetidin-1-yl)but-2- en-1-one“A219” (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(3,3-difluoroazetidin-1-yl)but-2-en-1-one “A220” (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-4-(pyrrolidin-1-yl)but-2-en- 1-one“A221” 1-(6-((6-amino-5-(4-(pyridin-3-yloxy)phenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)prop-2-en-1-one “A222”(E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidin-1-yl)but-2-en- 1-one“A223” (E)-1-(6-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-azaspiro[3.3]heptan-2-yl)-4-(3-fluoroazetidin-1-yl)but-2-en- 1-one“A224” (E)-N-(1,3-cis-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide “A225”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropipendin-1-yl)prop-2-en-1-one; compound(2)“A226” (E)-1-(2-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)-6-azaspiro[3.4]octan-6-yl)-4-(dimethylamino)but-2-en-1-one “A227”(E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-4-(dimethylamino)but-2-en-1-one “A228”(E)-N-(1,3-trans-3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide “A229”N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A230”(E)-N-(1,3-cis-3-((6-amino-5-(1-benzyl-1H-pyrazol-4-yl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but- 2-enamide“A231” (E)-1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)-3-phenylprop-2-en-1-one “A232”1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3- (dimethylamino)propan-l-one“A233” 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypipendln-1-yl)-3-(piperidin-1- yl)propan-1-one“A234” 1-((3S,4S)-4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-3-hydroxypiperidin-1-yl)-3-morpholinopropan- 1-one“A235” 1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)-3-(piperidin-1- yl)propan-1-one“A236” (E)-N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)-4-(dimethylamino)but-2-enamide “A237”N-(1,3-trans-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A238” N-(1,3-cis-3-((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)cyclobutyl)acrylamide “A239” 1-acryloyl-4-(((6-amino-5-(4-(3-(trifluoromethyl)phenoxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidine-4-carboxylic acid “A240”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2-fluoropheny)acrylamide “A241”N-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)phenyl)acrylamide “A242”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)oxy)phenyl)acrylamide“A243” N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3- yl)phenyl)acrylamide“A244” N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide “A245”N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5- yl)phenyl)acrylamide“A246” N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-4-fluorophenyl)acrylamide “A247”(R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A248”(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(dimethylamino)but-2-enamide “A249”N-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A250”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one; compound (1) “A251”N-(5-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)-2,4-difluorophenyl)acrylamide “A252”(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide “A253”1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A254”N-(3-((6-amino-5-(4-((2-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A255” N-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A256”N-(3-((6-amino-5-(4-(benzyloxy)-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A257”N-(3-((6-amino-5-(4-(benzyloxy)-2,3-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A258”4-(4-(3-acrylamidophenoxy)-6-aminopyrimidin-5-yl)-N- phenylbenzamide“A259” N-(3-((6-amino-5-(6-(benzyloxy)pyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A260”N-(3-((6-amino-5-(4-((3-fluorobenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A261”N-(3-((6-amino-2′-(benzyloxy)-[5,5′-bipyrimidin]-4-yl)oxy)phenyl)acrylamide “A262”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)pyrrolidin-1-yl)prop-2-en-1-one “A263”1-(4-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one “A264”N-(3-((6-amino-5-(4-((4-methoxybenzyl)oxy)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A265”(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-morpholinobut-2-enamide “A266”N-((1s,4s)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A267”N-(3-(4-((4-phenoxyphenyl)amino)pyridin-3- yl)phenyl)acrylamide 'A268”N-(3-((6-amino-5-(6-phenoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A269”1-(3-((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A270”N-(3-((3-(4-phenoxyphenyl)pyridin-4-yl)oxy)phenyl)acrylamide “A271”N-(3-((2-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)oxy)phenyl)acrylamide“A272” 3-(3-acrylamidophenyl)-4-(4-phenoxyphenoxy)picolinamide “A273”1-(3-(4-amino-6-((4-phenoxyphenyl)amino)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one “A274”(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-morpholinobut-2-enamide “A275”(S)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A276”N-((1r,4r)-4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)cyclohexyl)acrylamide “A277”N-(3-((6-amino-5-(4-fluoro-3-methoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A278”N-(3-((6-amino-5-(4-(2-hydroxypropan-2-yl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A279”1-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)prop-2-en-1-one “A280”N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4- yl)oxy)phenyl)acrylamide“A281” N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)acrylamide “A282”(E)-4-(dimethylamino)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide “A283”N-(3-(4-((4-phenoxyphenyl)amino)pyrimidin-5- yl)phenyl)acrylamide “A284”1-(3-((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A285”N-(3-((6-amino-5-(4-(pyrrolidine-1-carbonyl)phenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A286”1-(3-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A287”N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide “A288”1-(4′-(4-phenoxyphenoxy)-5,6-dihydro-[3,3′-bipyridin]-1(2H)-yl)prop-2-en-1-one “A289”N-(3-((6-amino-5-(4-isopropoxyphenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A290”(E)-N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(dimethylamino)but-2-enamide “A291”N-(3-((6-amino-5-(5-methoxypyridin-3-yl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A292”1-(4-(((6-amino-5-(4-(benzyloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A293”(E)-4-morpholino-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-enamide “A294”N-(3-((6-amino-5-(4-(benzyloxy)-2,6-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A295”(E)-N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-4-(4-(5-((4S)-2-oxohexahydro-1H-thieno[3,4-d]imidazol-4-yl)pentanoyl)piperazin-1-yl)but-2-enamide “A296”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2-ynamide “A297”N-(4-((3-(4-phenoxyphenyl)pyndin-4-yl)oxy)phenyl)acrylamide “A298”N-(1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)piperidin-3-yl)acrylamide “A299” 1-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)piperidin-1-yl)prop-2-en-1-one “A300”3-(3-aminophenyl)-4-(4-phenoxyphenoxy)pyridin-2-amine “A301”(E)-N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-4-(3,3-difluoropiperidin-1-yl)but-2-enamide “A302”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)acrylamide “A303”6-(4-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine “A304”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2-ynamide “A305”6-(3-aminophenoxy)-5-(4-phenoxyphenyl)pyrimidin-4-amine “A306”N-(3-(2-amino-4-(4-phenoxyphenoxy)pyrimidin-5- yl)phenyl)acrylamide“A307” (E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)but-2- enamide“A308” N-(4-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide “A309”N-((1-(6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)pipendin-3-yl)methyl)acrylamide “A310” N-(3-(2-amino-4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide “A311”(R)-N-(3-(4-amino-6-((1-phenylethyl)amino)pyrimidin-5-yl)phenyl)acrylamide “A312” 3-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline“A313” 4-(3-aminophenoxy)-3-(4-phenoxyphenyl)pyridin-2-amine “A314”4-(4-(4-phenoxyphenoxy)pyridin-3-yl)aniline “A315”(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine “A316”(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)methanamine “A317”5-(3-aminophenyl)-6-(4-phenoxyphenoxy)pyrimidin-4-amine “A318”N-(3-((3-(4-phenoxyphenyl)pyridin-4- yl)oxy)phenyl)propionamide “A319”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide “A320”N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)phenyl)propionamide “A321”N-(4-((3-(4-phenoxyphenyl)pyridin-4- yl)oxy)phenyl)propionamide “A322”N-(3-(4-(4-phenoxyphenoxy)pyridin-3- yl)phenyl)methacrylamide “A323”N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide “A324”N-(4-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)propionamide “A325”N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5- yl)phenyl)propionamide“A326” N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)propionamide “A327”(E)-N-(3-(4-(4-phenoxyphenoxy)pyridin-3-yl)benzyl)but-2- enamide “A328”3-(4-phenoxyphenyl)-4-(3-propionamidophenoxy)picolinamide “A329”N-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)phenyl)-1-cyanocyclopropanecarboxamide “A330”N-(3-(4-amino-6-(4-phenoxyphenoxy)pyrimidin-5-yl)phenyl)-1-cyanocyclopropanecarboxamide “A331”(E)-3-(7-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)naphthalen-2-yl)-N,N-dimethylacrylamide “A332”1-(4-(1-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)ethyl)piperidin-1-yl)prop-2-en-1-one “A333”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)propan-1-one “A334”1-(4-(((5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A335”1-(4-(((6-amino-5-(4-(pyridin-2-yloxy)phenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)prop-2-en-1-one “A336”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)piperidin-1-yl)but-2-yn-1-one “A337”N4-((1-(6-chloropyridin-2-yl)piperidin-4-yl)methyl)-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine “A338”1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)oxy)methyl)piperidin-1-yl)prop-2-en-1-one “A339”N-(3-((6-amino-5-(4-(benzyloxy)-2,5-difluorophenyl)pyrimidin-4-yl)oxy)phenyl)acrylamide “A340”N-(3-((2-amino-3-(4-phenoxyphenyl)pyridin-4- yl)oxy)phenyl)but-2-ynamide“A341” (R)-1-(3-((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)pyrrolidin-1-yl)but-2-yn-1-one “A342”N-{3-[6-Amino-5-(4-phenoxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloroacetamide “A343”N-(3-{6-Amino-5-[4-(2-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide “A344”N-(3-{6-Amino-5-[4-(4-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-acrylamide “A345”N-(3-{6-Amino-5-[4-(3-fluoro-benzyloxy)-phenyl]-pyrimidin-4-yloxy}-phenyl)-2-chloro-acetamide “A346”N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-propionamide “A347”N-{3-[6-Amino-5-(4-benzyloxy-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide “A348”N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide “A349”N-{3-[6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-acrylamide “A350”N-{3-(6-Amino-5-(4-benzyloxy-2-fluoro-phenyl)-pyrimidin-4- yloxy} -phenyl)-2-chloro-acetamide “A351”N-{3-[6-Amino-5-(4-benzyloxy-3-fluoro-phenyl)-pyrimidin-4-yloxy]-phenyl}-2-chloro-acetamide “A352”N-{4-[4-(3-Acryloylamino-phenoxy)-6-amino-pyrimidin-5-yl]-phenyl}-benzamide

In certain embodiments, the invention provides a method for thetreatment and/or prophylaxis of cancer, comprising administering to asubject a compound selected from:N-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A250); and1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one(A225).

In certain embodiments, the invention provides a method as describedabove, wherein the compound isN-[(1-acryloylpiperidin-4-Amethyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A250).

In certain embodiments, the invention provides a method as describedabove, wherein the compound is1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one(A225).

In certain embodiments, the method of the invention is used to treat orprevent a condition selected from a proliferative or hyperproliferativedisease, e.g., cancer.

In certain embodiments the invention provides a method of treating,preventing, or lessening the severity of cancer of a patient, byadministering a compound or composition of the present invention.

In certain embodiments, the invention provides for the treatment ofdiseases, disorders, and conditions characterized by excessive orabnormal cell proliferation. Such diseases include a proliferative orhyperproliferative disease. Examples of proliferative andhyperproliferative diseases include cancer and myeloproliferativedisorders.

In certain embodiments, the term “cancer” includes, but is not limitedto the following cancers. Oral: head and neck, including buccal cavity,lip, tongue, mouth, pharynx; Cardiac: sarcoma (angiosarcoma,fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma,fibroma, lipoma and teratoma; Lung: Non-small cell lung carcinomaincluding adenocarcinoma (acinar, bronchioloalveolar carcinoma[nonmucinous, mucinous, mixed], papillary, solid adenocarcionoma, clearcell, mucinous [colloid] adenocarcinorna, mucinous cystadenocarcinoma,signet ring, well-differentiated fetal), bronchioalveolar, squamous cellcarcinoma (basaloid, clear cell, papillary, small cell), large cell(undifferentiated) carcinoma (giant cell, basaloid, clear cell, largecell [with rhabdoid phenotype], large cell neuroendocrine carcinoma[LCNEC], combined LCNEC); small cell lung cancer including small cell(oat cell) carcinoma, combined small cell; adenoid cystic carcinoma;hamartoma; lymphoma; neuroendocrine/carcinoid; sarcoma.Gastrointestinal: esophagus (squamous cell carcinoma, larynx,adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma,leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma,glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel or smallintestines (adenocarcinoma, lymphoma, carcinoid tumors, Karposi'ssarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), largebowel or large intestines (adenocarcinoma, tubular adenoma, villousadenoma, hamartoma, leiomyoma), colon, colon-rectum, colorectal; rectum,Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor[nephroblastoma], lymphoma, leukemia), bladder and urethra (squamouscell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate(adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonalcarcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cellcarcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver:hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma,angiosarcoma, hepatocellular adenoma, hemangioma, biliary passages;Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibromna, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis deformans), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma);Female/Gynecological: uterus (endometrial carcinoma), cervix (cervicalcarcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma[serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, Sertoli-Leydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma), fallopian tubes (carcinoma), breast;Hematologic: blood (myeloid leukemia [acute and chronic], acutelymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferativediseases, multiple myeloma, myelodysplastic syndrome), Hodgkin'sdisease, non-Hodgkin's lymphoma [malignant lymphoma] hairy cell;lymphoid disorders; Skin: malignant melanoma, basal cell carcinoma,squamous cell carcinoma, Karposi's sarcoma, keratoacanthoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis,Thyroid gland: papillary thyroid carcinoma, follicular thyroidcarcinoma, undifferentiated thyroid cancer, medullary thyroid carcinoma,multiple endocrine neoplasia type 2A, multiple endocrine neoplasia type2B, familial medullary thyroid cancer, pheochromocytoma, paraganglioma;and Adrenal glands: neuroblastoma.

In certain embodiments, the cancer is selected from Non-Hodgkin'sLymphoma mantle cell lymphoma, and Non-Hodgkins's Lymphoma diffuse largeb-cell lymphoma, including abc subtype. In certain embodiments, thecancer is Non-Hodgkin's Lymphoma mantle cell lymphoma. In certainembodiments, the cancer is Non-Hodgkins's Lymphoma diffuse large b-celllymphoma. In certain embodiments, the cancer is Non-Hodgkins's Lymphomadiffuse large b-cell lymphoma, including abc subtype.

In certain embodiments, the cancer is selected from Non-Hodgkin'sLymphoma mantle cell lymphoma, and Non-Hodgkins's Lymphoma diffuse largeb-cell lymphoma, including abc subtype, and the compound is A250 orA225. In certain embodiments, the compound is A250. In certainembodiments, the compound is A225. In certain embodiments, the cancer isNon-Hodgkin's Lymphoma mantle cell lymphoma and the compound is A250 orA225. In certain embodiments, the compound is A250. In certainembodiments, the compound is A225. In certain embodiments, the cancer isNon-Hodgkins's Lymphoma diffuse large b-cell lymphoma and the compoundis A250 or A225. In certain embodiments, the compound is A250. Incertain embodiments, the compound is A225. In certain embodiments, thecancer is Non-Hodgkins's Lymphoma diffuse large b-cell lymphoma,including abc subtype, and the compound is A250 or A225. In certainembodiments, the compound is A250. In certain embodiments, the compoundis A225.

In general, all residues which occur more than once may be identical ordifferent, i.e. are independent of one another. Above and below, theresidues and parameters have the meanings indicated for Formula (I),Formula (II), Formula (III), Formula (IV) and Formula (V) unlessexpressly indicated otherwise. Accordingly, the invention relates, inparticular, to the compounds of Formula (I), Formula (II), Formula(III), Formula (IV) and Formula (V) in which at least one of the saidresidues has one of the preferred meanings indicated below.

The term “substituted” preferably relates to the substitution by theabove-mentioned substituents, where a plurality of different degrees ofsubstitution are possible, unless indicated otherwise.

All physiologically acceptable salts, derivatives, solvates, solvates ofsalts, and stereoisomers of these compounds, including mixtures thereofin all ratios, are also in accordance with the invention.

The compounds of the Formula (I), (II), (Ill), (IV) and (V) may have oneor more centres of chirality. They may accordingly occur in variousenantiomeric forms and be in racemic or optically active form. Theinvention therefore also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andhydrates and solvates of these compounds.

Since the pharmaceutical activity of the racemates or stereoisomers ofthe compounds according to the invention may differ, it may be desirableto use the enantiomers. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or evenemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Examples ofsuitable resolving agents are optically active acids, such as the R andS forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline), or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic enantiomer resolution with the aid of an opticallyactive resolving agent (for example dinitrobenzoylphenylglycine,cellulose triacetate or other derivatives of carbohydrates or chirallyderivatised methacrylate polymers immobilised on silica gel). Suitableeluents for this purpose are aqueous or alcoholic solvent mixtures, suchas, for example, hexane/isopropanol/acetonitrile, for example in theratio 82:15:3. An elegant method for the resolution of racematescontaining ester groups (for example acetyl esters) is the use ofenzymes, in particular esterases.

It is also contemplated that compounds of Formula (I), Formula (II),Formula (III), Formula (IV) and Formula (V) include isotope-labeledforms thereof. An isotope-labeled form of a compound of Formula (I),Formula (II), Formula (III), Formula (IV) and Formula (V) is identicalto this compound apart from the fact that one or more atoms of thecompound have been replaced by an atom or atoms having an atomic mass ormass number which differs from the atomic mass or mass number of theatom which usually occurs naturally. Examples of isotopes which arereadily commercially available and which can be incorporated into acompound of the Formula I by well-known methods include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F and³⁶Cl, respectively. It is also contemplated that a compound of theFormula I, a prodrug, thereof or a pharmaceutically acceptable salt ofeither which contains one or more of the above-mentioned isotopes and/orother iso-topes of other atoms are embodiments of the present invention.An isotope-labeled compound of the Formula I can be used in a number ofbeneficial ways. For example, an isotope-labeled compound of the FormulaI into which, for example, a radioisotope, such as ³H or ¹⁴C, has beenincorporated, is suitable for medicament and/or substrate tissuedistribution assays. These radioisotopes, i.e. tritium (³H) andcarbon-14 (¹⁴C), are particularly preferred owing to their ease ofpreparation and excellent detectability. Incorporation of heavierisotopes, for example deuterium (²H), into a compound of the Formula Imay have therapeutic advantages owing to the higher metabolic stabilityof this isotope-labeled compound. Higher metabolic stability translatesdirectly into an increased in vivo half-life or lower dosages, whichunder some circumstances would represent a preferred embodiment of thepresent invention. An isotope-labeled compound of the Formula I canadapted to the procedures disclosed in the synthesis schemes and therelated description, in the example part and in the preparation part inthe present text, replacing a non-isotope-labeled reactant by a readilyavailable isotope-labeled reactant.

In other embodiments it is contemplated that deuterium (²H) may beincorporated into a compound of Formula (I), Formula (II), Formula(III), Formula (IV) and Formula (V). Such deuterated compounds canmodify the oxidative metabolism of said deuterated compound by means theprimary kinetic isotope effect. The primary kinetic isotope effect is achange of the rate for a chemical reaction that results from exchange ofisotopic nuclei, which in turn is caused by the change in ground stateenergies necessary for covalent bond formation after this isotopicexchange. Exchange of a heavier isotope usually results in a lowering ofthe ground state energy for a chemical bond and thus causes a reductionin the rate in rate-limiting bond breakage. If the bond breakage occursin or in the vicinity of a saddle-point region along the coordinate of amulti-product reaction, the product distribution ratios can be alteredsubstantially. For explanation: if deuterium is bonded to a carbon atomat a non-exchangeable position, rate differences of k_(M)/k_(D)=2-7 aretypical. If this rate difference is observed in any compounds of Formula(I), Formula (II), Formula (III), Formula (IV) and Formula (V)susceptible to oxidation, the profile of this compound, in vivo, can bedrastically modified and result in improved pharmacokinetic properties.

When discovering and developing therapeutic agents, the person skilledin the art attempts to optimize pharmacokinetic parameters whileretaining desirable in vitro properties. It is reasonable to assume thatmany compounds with poor pharmacokinetic profiles are susceptible tooxidative metabolism. In vitro liver microsomal assays known in the aremay provide valuable information on the course of oxidative metabolismof this type, which in turn permits the rational design of deuteratedcompounds of Formula (I), Formula (II), Formula (III), Formula (IV) andFormula (V) with improved stability through resistance to said oxidativemetabolism. Significant improvements in the pharmacokinetic profiles ofcompounds of the Formula I may thereby be obtained, and can be expressedquantitatively in terms of increases in the in vivo half-life (t/2),concentration at maximum therapeutic effect (C_(max)), area under thedose response curve (AUC), and F; and in terms of reduced clearance,dose and materials costs.

While it is not intended that the present invention be limited to anydeuterated motif, the following is an example. A compound of Formula(I), Formula (II), Formula (III), Formula (IV) and Formula (V) which hasmultiple potential sites of attack for oxidative metabolism, for examplebenzylic hydrogen atoms and hydrogen atoms bonded to a nitrogen atom, isprepared as a series of analogues in which various combinations ofhydrogen atoms are replaced by deuterium atoms, so that some, most orall of these hydrogen atoms have been replaced by deuterium atoms.Half-life determinations enable favorable and accurate determination ofthe extent of the extent to which the improvement in resistance tooxidative metabolism has improved. In this way, it can be determinedthat the half-life of the parent compound may be extended by up to 100%as the result of deuterium-hydrogen exchange of this type.

Deuterium-hydrogen exchange in a compound of Formula (I), Formula (II),Formula (Ill), Formula (IV) and Formula (V) can also be used to achievea favorable modification of the metabolite spectrum of the startingcompound in order to diminish or eliminate undesired toxic metabolites.For example, if a toxic metabolite arises through oxidativecarbon-hydrogen (C—H) bond cleavage, it can reasonably be assumed thatthe deuterated analogue will greatly diminish or eliminate production ofthe unwanted metabolite, even if the particular oxidation is not arate-determining step. Further information on the state of the art withrespect to deuterium-hydrogen exchange may be found, for example inHanzlik et al., J. Org. Chem. 55, 3992-3997, 1990, Reider et al., J.Org. Chem. 52, 3326-3334, 1987, Foster, Adv. Drug Res. 14, 1-40, 1985,Gillette et al, Biochemistry 33(10) 2927-2937, 1994, and Jarman et al.Carcinogenesis 16(4), 683-688, 1993.

The compounds of the present invention can be in the form of a prodrugcompound. “Prodrug compound” means a derivative that is converted into abiologically active compound according to the present invention underphysiological conditions in the living body, e.g., by oxidation,reduction, hydrolysis or the like, each of which is carried outenzymatically, or without enzyme involvement. Examples of prodrugs arecompounds, wherein the amino group in a compound of the presentinvention is acylated, alkylated or phosphorylated, e.g.,eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein thehydroxyl group is acylated, alkylated, phosphorylated or converted intothe borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy,fumaryloxy, alanyloxy or wherein the carboxyl group is esterified oramidated, or wherein a sulfhydryl group forms a disulfide bridge with acarrier molecule, e.g. a peptide, that delivers the drug selectively toa target and/or to the cytosol of a cell. These compounds can beproduced from compounds of the present invention according to well-knownmethods. Other examples of prodrugs are compounds, wherein thecarboxylate in a compound of the present invention is for exampleconverted into an alkyl-, aryl-, choline-, amino, acyloxymethylester,linolenoyl-ester.

Metabolites of compounds of the present invention are also within thescope of the present invention.

Where tautomerism, e.g., keto-enol tautomerism, of compounds of thepresent invention or their prodrugs may occur, the individual forms,e.g., the keto or the enol form, are claimed separately and together asmixtures in any ratio. The same applies for stereoisomers, e.g.,enantiomers, cis/trans isomers, conformers and the like. If desired,isomers can be separated by methods well known in the art, e.g. byliquid chromatography. The same applies for enantiomers, e.g., by usingchiral stationary phases. Additionally, enantiomers may be isolated byconverting them into diastereomers, i.e., coupling with anenantiomerically pure auxiliary compound, subsequent separation of theresulting diastereomers and cleavage of the auxiliary residue.Alternatively, any enantiomer of a compound of the present invention maybe obtained from stereoselective synthesis using optically pure startingmaterials

The compounds of the present invention can be in the form of apharmaceutically acceptable salt or a solvate. The term“pharmaceutically acceptable salts” refers to salts prepared frompharmaceutically acceptable non-toxic bases or acids, includinginorganic bases or acids and organic bases or acids. In cases where thecompounds of the present invention contain one or more acidic or basicgroups, the invention also comprises their correspondingpharmaceutically or toxicologically acceptable salts, in particulartheir pharmaceutically utilizable salts. Thus, the compounds of thepresent invention which contain acidic groups can be present in saltform, and can be used according to the invention, for example, as alkalimetal salts, alkaline earth metal salts or as ammonium salts. Moreprecise examples of such salts include sodium salts, potassium salts,calcium salts, magnesium salts or salts with ammonia or organic aminessuch as, for example, ethylamine, ethanolamine, triethanolamine or aminoacids. Compounds of the present invention which contain one or morebasic groups, i.e. groups which can be protonated, can be present insalt form, and can be used according to the invention in the form oftheir addition salts with inorganic or organic acids. Examples ofsuitable acids include hydrogen chloride, hydrogen bromide, phosphoricacid, sulfuric acid, nitric acid, methanesulfonic acid,p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, aceticacid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formicacid, propionic acid, pivalic acid, diethylacetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid,sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid,isonicotinic acid, citric acid, adipic acid, and other acids known tothe person skilled in the art. If the compounds of the present inventionsimultaneously contain acidic and basic groups in the molecule, theinvention also includes, in addition to the salt forms mentioned, innersalts or betaines (zwitterions). The respective salts can be obtained bycustomary methods which are known to a person skilled in the art, forexample by contacting these with an organic or inorganic acid or base ina solvent or dispersant, or by anion exchange or cation exchange withother salts. The present invention also includes all salts of thecompounds of the present invention which, owing to low physiologicalcompatibility, are not directly suitable for use in pharmaceuticals butwhich can be used, for example, as intermediates for chemical reactionsor for the preparation of pharmaceutically acceptable salts.

Furthermore, the present invention relates to pharmaceuticalcompositions comprising a compound of the present invention, or aprodrug compound thereof, or a pharmaceutically acceptable salt orsolvate thereof as an active ingredient together with a pharmaceuticallyacceptable carrier.

“Pharmaceutical composition” means one or more active ingredients, andone or more inert ingredients that make up the carrier, as well as anyproduct which results, directly or indirectly, from combination,complexation or aggregation of any two or more of the ingredients, orfrom dissociation of one or more of the ingredients, or from other typesof reactions or interactions of one or more of the ingredients.Accordingly, the pharmaceutical compositions of the present inventionencompass any composition made by admixing a compound of the presentinvention and a pharmaceutically acceptable carrier.

A pharmaceutical composition of the present invention may additionallycomprise one or more other compounds as active ingredients, such as oneor more additional compounds of the present invention, or a prodrugcompound or other BTK inhibitors.

The pharmaceutical compositions include compositions suitable for oral,rectal, topical, parenteral (including subcutaneous, intramuscular, andintravenous), ocular (ophthalmic), pulmonary (nasal or buccalinhalation), or nasal administration, although the most suitable routein any given case will depend on the nature and severity of theconditions being treated and on the nature of the active ingredient.They may be conveniently presented in unit dosage form and prepared byany of the methods well-known in the art of pharmacy.

In one embodiment, said compounds and pharmaceutical composition, orpharmaceutically acceptable salt, prodrug or hydrate thereof, and apharmaceutically acceptable carrier, are for the treatment of cancer.

The invention also relates to the use of compounds according to theinvention for the preparation of a medicament for the treatment ofcancer.

In practical use, the compounds of the present invention can be combinedas the active ingredient in intimate admixture with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending on the form ofpreparation desired for administration, e.g., oral or parenteral(including intravenous). In preparing the compositions for oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols, flavoring agents,preservatives, coloring agents and the like. In the case of oral liquidpreparations, any of the usual pharmaceutical media may be employed,such as, for example, suspensions, elixirs and solutions; or carrierssuch as starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents and thelike. In the case of oral solid preparations the composition may takeforms such as, for example, powders, hard and soft capsules and tablets,with the solid oral preparations being preferred over the liquidpreparations.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form in which case solidpharmaceutical carriers are obviously employed. If desired, tablets maybe coated by standard aqueous or nonaqueous techniques. Suchcompositions and preparations should contain at least 0.1 percent ofactive compound. The percentage of active compound in these compositionsmay, of course, be varied and may conveniently be between about 2percent to about 60 percent of the weight of the unit. The amount ofactive compound in such therapeutically useful compositions is such thatan effective dosage will be obtained. The active compounds can also beadministered intranasally as, for example, liquid drops or spray.

The tablets, pills, capsules, and the like may also contain a bindersuch as gum tragacanth, acacia, corn starch or gelatin; excipients suchas dicalcium phosphate; a disintegrating agent such as corn starch,potato starch, alginic acid; a lubricant such as magnesium stearate; anda sweetening agent such as sucrose, lactose or saccharin. When a dosageunit form is a capsule, it may contain, in addition to materials of theabove type, a liquid carrier such as a fatty oil.

Various other materials may be present as coatings or to modify thephysical form of the dosage unit. For instance, tablets may be coatedwith shellac, sugar or both. A syrup or elixir may contain, in additionto the active ingredient, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor.

Compounds of the present invention may also be administeredparenterally. Solutions or suspensions of these active compounds can beprepared in water suitably mixed with a surfactant such ashydroxy-propylcellulose. Dispersions can also be prepared in glycerol,liquid polyethylene glycols and mixtures thereof in oils. Under ordinaryconditions of storage and use, these preparations contain a preservativeto prevent the growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g., glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

Any suitable route of administration may be employed for providing amammal, especially a human, with an effective dose of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like. Preferably compounds of thepresent invention are administered orally.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

In certain aspects, the invention provides a capsule comprising thecompound as described above. In certain embodiments, the capsulecomprises about 20 mg to about 100 mg of the compound of the invention.In certain embodiments, the capsule comprises about 80 mg of thecompound of the invention. In certain embodiments, the capsule comprisesabout 160 mg of the compound of the invention. In certain embodiments,the capsule comprises about 600 mg of the compound of the invention. Incertain embodiments, the capsule comprises about 900 mg of the compoundof the invention. In certain embodiments, the compound isN-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A250) or1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one(A225). In certain embodiments, the compound isN-[(1-acryloylpiperidin-4-yl)methyl]-5-(4-phenoxyphenyl)pyrimidine-4,6-diamine(A250). In certain embodiments, the compound is1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-one(A225).

In certain aspects, the invention is directed towards a method oftreating a cancer as described herein, comprising the step ofadministering to a subject the capsule, as described above, once perday. In certain embodiments, the cancer is Relapsed/Refractory B CellMalignancies. In certain embodiments, the cancer is selected fromNon-Hodgkin's Lymphoma mantle cell lymphoma, and Non-Hodgkins's Lymphomadiffuse large b-cell lymphoma, including abc subtype.

The invention also relates to a set (kit) consisting of separate packsof

a) an effective amount of a compound according to the invention or aphysiologically acceptable salt, solvate or prodrug thereof, and

b) an effective amount of a further medicament active ingredient.

The set comprises suitable containers, such as boxes, individualbottles, bags or ampoules. The set may, for example, comprise separateampoules, each containing an effective amount of a compound according tothe invention and/or pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilised form.

EXEMPLIFICATION

As depicted in the Examples below, in certain exemplary embodiments,compounds are prepared according to the following general procedures. Itwill be appreciated that, although the general methods depict thesynthesis of certain compounds of the present invention, the followinggeneral methods, and other methods known to one of ordinary skill in theart, can be applied to all compounds and subclasses and species of eachof these compounds, as described herein.

Compound numbers utilized in the Examples below correspond to compoundnumbers set forth supra.

Example 1 Mosaic Spot Assay (CLL Patient Samples)

The Mosaic Spot Assay was conducted in accordance with MosaicLaboratories' SOPs. The CLL blood and bone marrow mononuclear cells wereevaluated for viability and cell count prior to plating in Mosaic SpotMedia (X-Vivo 10 Media [Lonza, Fisher Scientific, Carlsbad, Calif.]+10%FBS [Life Technologies, Carlsbad, Calif.]) in a 96-well cytophobic platein the presence of compounds and two controls: 1) a cytotoxic dose ofcisplatin serving as a positive control; and 2) no drug treatmentserving as a reference and negative control. Tumor cells were placed ina humidified 37° C. incuba tor with 5% CO2 for 4 days. At the end of theincubation, cells were removed and cytocentrifuged onto positive chargedglass slides (Superfrost+, VWR, Radnor, Pa.). Slides were stained withWright Giemsa in accordance with Mosaic Laboratories SOPs. Cell growthwas measured by a hematopathologist. The results are provided in FIG. 1.

Example 2 MCL/ABC-DLBCL Cell Lines

Cell lines that were preserved in liquid nitrogen were thawed andexpanded in growth media containing full serum. Once cells reachedexpected doubling times, screening began. Cells were seeded in growthmedia in black 384-well tissue culture treated plates. Cells wereequilibrated in assay plates via centrifugation and placed in incubators(attached to the Dosing Modules) at 37° C. for twenty-four hours beforetreatment. At the time of treatment, a set of assay plates (which do notreceive treatment) were collected and ATP levels were measured by addingATPLite (Perkin Elmer). These Tzero (T₀) plates were read usingultra-sensitive luminescence on Envision plate readers. Assay plateswere incubated with compound for seventy-two hours and were analyzedusing ATPLite. All data points were collected via automated processesand were subject to quality control and analyzed using Horizon'sproprietary software. Assay plates were accepted if they passed thefollowing quality control standards: relative raw values were consistentthroughout the entire experiment, Z-factor scores were greater than 0.6and untreated/vehicle controls behaved consistently on the plate.

Horizon utilized Growth Inhibition (GI) as a measure of cell growth. TheGI percentages were calculated by applying the following test andequation:

${{If}\mspace{14mu} T} < {V_{0}\text{:}\mspace{14mu} 100*\left( {1 - \frac{T - V_{0}}{V_{0}}} \right)}$$\;{{{If}\mspace{14mu} T} \geq {V_{0}\text{:}\mspace{14mu} 100*\left( {1 - \frac{T - V_{0}}{V - V_{0}}} \right)}}$where T is the signal measure for a test article at seventy-two hours, Vis the untreated/vehicle-treated control measure, and V_(o) is theuntreated/vehicle control measure at time zero (also colloquiallyreferred as T₀ plates). This formula was derived from the GrowthInhibition calculation used in the National Cancer Institute's NCI-60high throughput screen.

A GI reading of 0% represents no growth inhibition and occurred ininstances where the T reading at seventy-two hours were comparable tothe V reading at the respective time period. A GI 100% representscomplete growth inhibition (cytostasis) and in this case cells treatedwith compound for seventy-two hours had the same endpoint reading as T₀control cells. A GI of 200% represents complete death (cytoxicity) ofall cells in the culture well and in this case the T reading atseventy-two hours was lower than the T₀ control (values near or atzero). These GI calculations were used in all single agent andcombination data analysis, and the results are found in FIGS. 2 and 3.

What is claimed is:
 1. A method of treating a myeloproliferativedisorder in a human subject, comprising: administering a therapeuticallyeffective amount of a compound of the formula1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-oneor a pharmaceutically acceptable salt thereof to the human subject, thehuman subject having or suspected of having the myeloproliferativedisorder.
 2. The method of claim 1, wherein the compound of the formula1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-oneis administered to the human subject.
 3. The method of claim 1, whereinthe pharmaceutically acceptable salt of the compound of the formula1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-oneis administered to the human subject.
 4. The method of claim 1, whereinthe compound or the pharmaceutically acceptable salt thereof isadministered to the human subject orally.
 5. The method of claim 1,wherein the compound of the formula1-(4-(((6-amino-5-(4-phenoxyphenyl)pyrimidin-4-yl)amino)methyl)-4-fluoropiperidin-1-yl)prop-2-en-1-oneor the pharmaceutically acceptable salt thereof is administered as apharmaceutical composition comprising the compound and at least onepharmaceutical carrier.
 6. The method of claim 5, wherein thepharmaceutical composition comprises about 20 mg to about 100 mg of thecompound.
 7. The method of claim 6, wherein the pharmaceuticalcomposition comprises 20 mg of the compound.
 8. The method of claim 6,wherein the pharmaceutical composition comprises 50 mg of the compound.9. The method of claim 6, wherein the pharmaceutical compositioncomprises 80 mg of the compound.
 10. The method of claim 6, wherein thepharmaceutical composition comprises 100 mg of the compound.
 11. Themethod of claim 5, wherein the pharmaceutical composition comprisesabout 160 mg of the compound.
 12. The method of claim 5, wherein thepharmaceutical composition comprises about 600 mg of the compound. 13.The method of claim 5, wherein the pharmaceutical composition comprisesabout 900 mg of the compound.
 14. The method of claim 5, wherein thepharmaceutical composition is a capsule containing the compound.
 15. Themethod of claim 5, wherein the pharmaceutical composition isadministered to the human subject orally.
 16. The method of claim 5,wherein the pharmaceutical composition is administered twice daily. 17.The method of claim 1, wherein the compound is administered at aconcentration in a range from 0.04 μM up to and including 25 μM in aunit dosage form.
 18. The method of claim 17, wherein at least 50% oftumor cell growth is inhibited.
 19. The method of claim 17, wherein thecompound is administered at a concentration in a range from 5 μM up toand including 25 μM in a unit dosage form.
 20. The method of claim 19,wherein at least 70% of tumor cell growth is inhibited.
 21. The methodof claim 1, wherein after at least 72 hours of administration of thecompound, an average percent growth inhibition of tumor cells is in arange from 4% up to and including 28%.
 22. The method of claim 1,wherein the compound is administered in a range from 7.5 mg of compoundper kg of weight of subject up to and including 25 mg of compound per kgof weight of subject.
 23. The method of claim 22, wherein the compoundis administered once daily.
 24. The method of claim 22, wherein tumorvolume is reduced by at least 40% fifteen days after treatment with thecompound as compared to an untreated tumor.
 25. The method of claim 22,wherein tumor volume is reduced by at least 75% twenty-five days aftertreatment with the compound as compared to an untreated tumor.